Single modality radiotherapy or primary surgery (transoral or open resection) for stage T1-2 N0-1 has been preferred with similar rates of local control and survival, as no prospective randomized comparison is present [1–3]. Concurrent chemoradiotherapy is mostly the key treatment for locally advanced stages III and IVA/B cancers without distant metastases (Table 7.1) [4–11], while the resectability and neck nodal disease volume are denominators in decision making to perform initially surgery for primary (T3–T4a) and neck (N0-1) and to consolidate with radiotherapy (close resection margins, lymphovascular and perineural invasion , pT3-T4, N2 or N3, nodal disease levels IV–V) or chemoradiotherapy (positive surgical margins and/or nodal extracapsular invasion) metastases (Table 7.2) [12–15]. Induction chemotherapy followed by radio/chemoradiotherapy is yet a category three approach which might be considered in heavy nodal volume with an increased risk of distant metastases [5, 6, 16–19]. Cetuximab as a single agent concurrent with radiotherapy for treatment of locoregionally advanced head and neck cancer seemed to improve locoregional control and to reduce mortality, while the addition of cetuximab to the chemoradiotherapy with cisplatin did not improve progression-free or overall survival [20].

It has become evident as one of the most significant recent advances that HPV-positive oropharyngeal cancer (HPVOPC) should be considered as a different entity from HPV-negative cancers [21]. HPVOPC is frequently presenting with a smaller primary tumor and more advanced cervical lymph node disease which is having a cystic appearance [22–24].

Oropharyngeal cancer has been recommended to be classified as having a low (HPV+, ≤10 pack-year smoking or >10 pack-year and N0–N2a), intermediate (HPV+, >10 pack-year smoking and N2b–N3 or HPV-, ≤10 pack-year smoking, T2–3), or high risk (HPV-, ≤10 pack-year smoking, T4 or HPV-, >10 pack-year smoking) of death on the basis of four factors [25, 26]. However, as the results of ongoing trials for metastases (Table 7.3) are incomplete, current recommendation should be treatment regardless of the HPV status according to the stage of disease at presentation.

Oropharynx is shaped with following structures: palatoglossal arch, pharyngeal tonsil, tonsillar fossa, tonsillar pillar, palatopharyngeal arch, base of the tongue, epiglottic vallecula , posterior wall of the oropharynx, and oral surface of the soft palate, uvula. The most common locations for a primary tumor of the oropharynx are anterior tonsillar pillar and tonsil. Primary lymphatic drainage is the retropharyngeal, level II and III nodes.